The present invention generally relates to certain compounds useful as platelet aggregation inhibitory agents.
Antithrombotic agents are substances that prevent the formation of a thrombus. There are two different types of thrombi; venous thrombus and arterial thrombus. The first is the red thrombus which consists of a fibrin network entrapping the formed elements of the blood. The second one is the white thrombus which is composed mainly of platelets. All forms of venous thrombus and embolism result from red thrombus. Thrombotic and thromboembolic events, which manifest as myocardial infarction and stroke, remain the leading cause of death and disability in the United States.
Thromboembolic disorders have been shown to be directly related to the susceptibility of blood platelets to adenosine diphosphate and thrombin induced platelet aggregation and to other adhesion-release-aggregation chain reactions. Certain animal species wearing prosthetic devices or whose blood is exposed to biomaterials during renal dialysis, blood oxygenation, cardiac catheterization, etc. are especially predisposed to thromboembolic disorders.
Certain chemical compounds are known to inhibit platelet aggregation and are classified as antithrombotic agents. Many of these compounds are not employed, however, because of their alternative therapeutic effects. Drugs that have shown activity in inhibiting platelet aggregation belong to the following chemical groups:
1. Arylakanoic acids & derivatives: e.g. ibuprofen;
2. Clofibric acid derivatives: e.g. clofibrate;
3. Dextrans: e.g. dextran 40;
4. Imidazole derivatives & isosteres: e.g. dazmegrel;
5. Prostaglandins: e.g. azaprostanoic acid;
6. Phthalazinecarboxylic acid derivatives: e.g. anagrelide;
7. Pyrazole derivatives: e.g. sulfinpyrazone, nafazatrom;
8. Pyrimidine derivatives: e.g. dipyridamole;
9. Salicylates: e.g. aspirin;
10. Miscellaneous structures: e.g. amipizone, cilostazol, ticlopidine, bencyclane, picotamide, etc.
Inhibitors of platelet aggregation generally act by one of the following mechanisms: (1) inhibition of arachidonic acid-dependent aggregation: (a) cyclooxygenase inhibitors: arylalkanoic acids and derivatives, pyrazole derivatives, and salicylates; (b) thromboxane synthetase inhibitors: imidazole derivatives and isosteres, and phthalazinecarboxylic acid derivatives; (c) thromboxane A.sub.2 antagonists; (d) prostacyclin activator: nafazatrom; or (2) inhibition of arachidonic acid-independent aggregation: (a) cyclic AMP phosphodiesterase inhibitors; cilostazol, and pyrimidine derivatives; (b) adenylate cyclase activators; prostaglandins and ticlopidine.
Accordingly, it is known that a large series of aryl and alkyl bis-piperidine compounds exhibit platelet aggregation inhibitory activity, as described by U.S. Pat. Nos. 4,634,709 and 4,657,917. While the exact mechanism of action is not clearly understood, the amphiphilic structure of these compounds suggests that they may insert themselves into the plasma membrane and other membrane bilayers and interrupt normal transmembrane ion-mediated signals which would normally lead to platelet aggregation. These events, being devoid of ligand-receptor interactions or enzyme inhibition, are not generally thought of as being dependent on the chiral influences of the active agents. The present inventors have, however, unexpectedly discovered that the optical isomers of such compounds are not equipotent.
It is therefore an object of the present invention to provide a composition and method for inhibiting blood platelet aggregation thereby being useful for the treatment of thromboembolic disorders.
It is a further object of the invention to provide a stereoisomer of anti-thromboembolic compound with an improved ratio of therapeutic potency to toxicity.